Genes: VHL (Von Hippel-Lindau)

  • loss of function is associated with the Von Hippel-Lindau disease
  • Product of the VHL gene is the protein pVHL.
  • Function of pVHL is ubiquitylation of HIF-1α, which is one of two subunits of the HIF-1(hypoxia-inducible factor-1) transcription factor.
  • Polyubiquitylation of HIF-1α leads to its degradation and therefore prevents the formation of a functional HIF-1.
  • A functional HIF-1 transcription factor causes expression of genes such as VEGF, PDGF, TGF-α, which are growth promoting genes in the context of establishing new blood vessels.
  • Normally, pVHL constitutively prevents HIF-1 to become active, but if the cell experiences hypoxia, pVHL fails to bind to the HIF-1α subunit and therefore an adequate stimulation of angiogenesis and erythropoiesis will establish an sufficient oxygen supply for the cells suffering hypoxia.
  • If pVHL cannot form, since VHL was deactivatied by (e.g.) mutation, HIF-1α is constitutively active, which leads to an inappropriate high level of these growth factors, which will favor tumor growth.
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